title: 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
abstract: The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
authors.affiliation: Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. lzhi@ligand.com
authors.forename: L
authors.initials: L
authors.lastname: Zhi
authors.forename: C M
authors.initials: CM
authors.lastname: Tegley
authors.forename: E A
authors.initials: EA
authors.lastname: Kallel
authors.forename: K B
authors.initials: KB
authors.lastname: Marschke
authors.forename: D E
authors.initials: DE
authors.lastname: Mais
authors.forename: M M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: T K
authors.initials: TK
authors.lastname: Jones
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D011804:Quinolines; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone